Device and method for treatment of infections

ABSTRACT

A packing material for the treatment of infections, particularly of the teeth and gums. A biocompatible, polymeric carrier material, typically calcium alginate, has dispersed therein an antibiotic ester which typically defines at least one ester group of 10 to 18 carbon atoms per molecule. The antibiotic ester is present in the polymeric carrier in an initial concentration sufficient to allow the continuous, controlled release of at least an inhibitory concentration of free antibiotic as a hydrolysis product from the antibiotic ester. The rate of release of free antibiotic is influenced by the presence of bacterial lipase, so that a higher concentration of infectious bacteria causes the release of higher concentrations of free antibiotic, hydrolyzed from the ester, in a feedback loop.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional application of pending application Ser.No. 07/563,394 filed Aug. 6 1990 now U.S. Pat. No. 5,186,936.

BACKGROUND OF THE INVENTION

Goodson U.S. Pat. No. 4,764,377 describes an intra-pocket drug deliverydevice for the treatment of periodontal disease. The therapeutic agentdelivery device may be packed into a periodontal pocket formed in thegum tissue against the root of the tooth where a chronic infection suchas pyorrhea exists. The packing material of the Goodson patent is astring-like polymeric material which carries a concentration of anantibiotic such as teiracycline for controlled release of thetetracycline over a period of time into the periodontal cavity. By thistechnique, a continuous delivery of an antibiotic may be provided forthe elimination of chronic infection.

Additionally, the Goodson patent teaches a diffusion limiting surfaceabout a stringlike therapeutic agent delivery device, apparently tocontrol the rate of diffusion of tetracycline or other antibiotic fromthe plastic material in which it resides.

As one disadvantage of the above system, the antibiotic which diffusesout of the polymeric carrier will rapidly disperse out of theperiodontal pocket by diffusion through the tissue. Also, the rate ofantibiotic diffusion is of course constant and predictable whether ornot there is a substantial concentration of bacteria present or not.

It would be desirable to provide a controlled release vehicle forantibiotics in a packing material for the treatment of infections inwhich the diffusion rate of antibiotic can be effectively slowed, butthat the concentration of free antibiotic present can increase in amanner which is dependent upon the concentration of bacteria present.Thus, in a chronic situation when bacterial infections may appear anddisappear, such a packing material would tend to retain its supply ofantibiotic when the concentration of harmful bacteria present was verylow, but the release of free antibiotic would increase as theconcentration of bacteria increased. This would form a long-lived,self-regulating system to keep the area containing the packing materialsubstantially free of infection.

Such a system is provided in accordance with this invention, in which aminimum, desired concentration of free antibiotic is released undercircumstances where the bacteria concentration is low, but in the eventof significant infection the release of antibiotic from the packingmaterial of this invention can increase in response to the infectiousconditions. Thus, the packing material of this invention can have alonger useful life when placed in an infection-prone tissue pocket orthe like, since under conditions of low bacterial concentration a lowconcentration of free antibiotic is released. However, but when the needarises, higher amounts of antibiotic are released in response to higherconcentrations of bacteria present.

Additionally, in this invention the antibiotic may be stored in aprodrug form which, if it diffuses from the packing material, is lesspermeable through tissue, so that it tends to be retained in the bodycavity into which it is released.

DESCRIPTION OF THE INVENTION

In this invention, a packing material is provided for the treatment ofinfections, particularly infections of the teeth and gums, although itis contemplated to be also useful in other situations as well. By thisinvention, a biocompatible, polymeric carrier material is provided,carrying therein an antibiotic ester which defines at least one estergroup of typically 10 to 18 carbon atoms per molecule.

The term "antibiotic ester" relates to any conventional, medicallyavailable antibiotic which has at least one hydroxyl or carboxylic acidgroup which is capable of undergoing an eaterification reaction with anappropriate carboxylic acid or alcohol having 10 to 18 carbon atoms, sothat the antibiotic eater defines a pendent ester group which is theresidue of such carboxylic acid or alcohol having 10 to 18 carbon atoms.The antibiotic ester serves as a prodrug which may be activated byhydrolysis of the ester group from the antibiotic to restore it to theoriginal antibiotic form.

The antibiotic ester can diffuse from the biocompatible polymericcarrier after implantation in a body tissue before its hydrolysis, orthe antibiotic ester may be hydrolyzed within the polymeric carrier, andthe free antibiotic can diffuse out into the body tissue. Typically, theantibiotic ester that diffuses from the carrier tends to have lowertissue permeability than the free antibiotic, so it tends to remain inthe body cavity in which the polymeric carrier material resides until itis hydrolyzed. The effect of this is to decrease the outward diffusionof the antibiotic that is present for greater dosage efficiency in thebody cavity over a long term period.

The antibiotic ester is present in the polymeric carrier, typicallybeing distributed throughout the mass of the polymeric carrier either asa solid solution or as small particles of antibiotic ester, in aninitial concentration which is sufficient to allow the continuous,controlled release of typically at least an inhibitory concentration offree antibiotic as a hydrolysis product from the antibiotic ester inresponse to the presence of bacterial lipase. Many bacteria which areassociated with infection produce a lipase enzyme which serves topromote the hydrolysis of ester groups. Thus, the release of freeantibiotic will be dependent at least in part on the titer of bacteriapresent around the packing material packed in a body cavity. If theconcentration of bacteria is low, the presence of bacterial lipase iscorrespondingly low, and the release of free antibiotic from the packingmaterial will be low. If infectious conditions are present, theconcentration of bacterial lipase will be higher, resulting in a morerapid rate of ester group cleavage, so that a higher concentration offree antibiotic will be present.

Preferably, the minimum inhibitory concentration of free antibioticwhich is continuously released by the packing material of this inventionwill be essentially equivalent in its antibacterial effect to at least 3micrograms per ml. of the antibiotic metronidazole, which is a preferredantibiotic for use in this invention. As stated above, in the presenceof infectious levels of bacteria concentration, the release by diffusionand hydrolysis of free antibiotic may result in a concentrationsubstantially higher than the above, while a diminution of theconcentration of bacteria through the effect of the antibiotic willcause a spontaneous reduction in the concentration of free antibioticpresent. Thus, the packing material of this invention releases freeantibiotic in an economical manner which can be tailored to an optimumclinical program for the treatment of chronic infections, particularlythose of the type found in gum disease.

Preferably, the concentration of antibiotic ester in the biocompatible,polymeric carrier may range from about 10 to 150 percent by weight,based on the polymeric carrier present.

The biocompatible polymers used herein May be any of a wide variety,such as those described in the above cited Goodson patent. Preferablycalcium or magnesium alginate is used, or other hydrogels such aspectin, chitosan, or chitin.

The palmitate (16 carbon) ester of metronidazole is a preferredantibiotic ester for use in this invention, while the current mostpreferred biocompatible, polymeric carrier material comprises calciumalginate. Metronidazole palmitate disperses relatively easily in calciumalginate and is stable therein, but for the diffusion and hydrolysisprocesses which result in free antibiotic delivery in accordance withthis invention. If desired, free antibiotic may also be added to thepolymeric carrier to provide a bolus of initial antibiotic release,since the free antibiotic will diffuse out of the system faster thanantibiotic eater, to develop an immediate concentration of antibiotic inthe tissue adjacent the implanted packing material until the slowerdiffusion and hydrolysis processes of the antibiotic ester get underway.

It should be understood that while antibiotic esters in which the estergroup has fewer carbon atoms, (6 or less) are known for use in themedical field, their purpose was to improve the topical delivery of adrug by means of esterification so that its transmissibility through theskin would increase. In this invention, the use of higher eater groupstends to decrease the diffusability of the esterified drugs throughtissue, to cause an increase in the concentration of antibiotic in thetissue pocket in which the packing material resides during use.

Metronidazole palmitate is released from a calcium alginate polymericcarrier material in high quantities, and reacts in the presence oflipase enzymes to provide free metronidazole with a hydrolysis rategenerally proportional to the enzyme concentration. At lower enzymeconcentrations on the order of no more than 0.4 milligrains per ml. ofliquid media, a lag period may be noted of several hours before thehydrolysis reaction is noted, showing that the antibiotic may be spared,and retained adjacent the packing material, when the tissue surroundingthe packing material is not infected. Other esters of metronidazole andother antibiotics in accordance with this invention can also providesimilar results.

Likewise, the twenty four hour release of metronidazole frommetronidazole palmitate diffused in calcium alginate strings issubstantially directly proportional to the loading of metronidazolealginate in the string.

The polymeric carrier may be of any desired shape, preferably being ofstring or fibrous form. The string or fiber used as the polymericcarrier material containing an antibiotic ester may be a solid string orfiber, or a hollow string or fiber having a lumen. If desired, the lumenmay contain a relatively large supply of antibiotic ester in accordancewith this invention or another medicament, or a mixture thereof. Theinner core of the fiber, (the terms "string" and "fiber" beingsynonymous) may contain as a polymeric carrier a hydrogel which definesionic polymer units of one charge, positive or negative, and, of course,accompanying simple ions of the other charge such as calcium orchloride. The fiber also may define an outer coating which comprises ahydrogel which defines ionic polymer units of the opposite charge tothat of the hydrogel of the inner core. The antibiotic ester issubstantially carried in the inner core, and/or in a lumen defined inthe inner core, while the outer coating acts as a controlled releasebarrier to limit generation of free antibiotic. Thus, by control of theouter coating, the antibiotic release rates of the packing material ofthis invention may be controlled to conform to a large variety ofdesirable clinical programs.

For example, the inner core may comprise an alginate salt such ancalcium or magnesium alginate, while the outer coating comprises amaterial such as pectin, chitosan, or chitin.

Alternatively, the packing material of this invention may be a fiberwhich comprises an inner core of a hydrogel polymeric carrier whichdefines ionic polymer units, for example calcium alginate. The samefiber may have an outer coating which comprises a mixture of 70 to 95parts by weight of poly(lysine) or other related polypeptide, and 5 to30 parts by weight when applied of a polyel-type plasticizer for thepoly(lysine). The term "when applied" means that the mixture ofpoly(lysine) and plasticizer as described above is the mixture when itis just applied to the inner core of the fiber. Upon contact with water,the polyel-type plasticizer will of course dissolve away, and it mayevaporate upon storage, resulting in an outer coating which acts as acontrolled release barrier to limit generation of the free antibiotic.

The polyol plasticizer is present primarily to define small apertures inthe outer coating, which serves to permit a limited amount of release ofthe antibiotic ester or free antibiotic, since the plasticizer, if itstill remains, will be quickly leached away after implantation in atissue pocket. It thus follows that higher concentrations of polyol-typeplasticizers will result in an outer coating that is more permeable tothe antibiotic and antibiotic ester than an outer coating with lowerconcentrations of polyol plasticizer, so that predetermined releasecharacteristics may be built into the system.

Examples of polyel-type plasticizers which may be used includeglycerine, sorbitol, and/or polyethylene glycol. In this situation, thepreferred hydrogel for the inner core is calcium alginate.

As yet another embodiment, such a fiber may also carry an outermost,hydrophilic alginate layer such as sodium or potassium alginate, toprovide a smooth, hydrophilic surface. Additionally, the outer layer maybe calcium or magnesium alginate.

Additional ingredients which may be added to the packing materials ofthis invention include an agent for either x-ray or optical visibilitysuch as barium sulfate or fluorescein. Likewise, as stated before, freeantibiotic may be added.

Additionally, the above-described packing materials which include aninner core and an outer coating may be used for othercontrolled-diffusion purposes besides those specifically described inthis invention, for example, for the controlled diffusion of freeantibiotic without esterification, or for the controlled diffusion ofother medicaments and nutrients such as vitamins, hormones, heparin, andthe like at an implantation site.

The above disclosure and the examples below are offered for illustrativepurposes only, and are not intended to limit the scope of the inventionof this application, which is as described in the claims below.

Example 1

Thirty ml. of 0.5 percent (w/v) sodium alginate solution was prepared.To this solution was added, with vigorous mixing, an amount ofmetronidazole palmitate sufficient to provide to the solution a quantityof 210 micrograms per ml. of metronidazole upon complete hydrolysis ofthe ester. Metronidazole palmitate is made by an esterification reactionbetween metronidazole and palmitic acid.

The solution was well mixed, and one ml. portions of the suspension ofmetronidazole palmitate in the solution were drawn up into a syringeequipped with a 16 gauge needle. The one ml. portions were then injectedthrough the needle in a steady stream into a one molar calcium chloridesolution, to form strings of calcium alginate about 7 cm. in length and0.5 mm. in diameter, which strings contained the dispersed metronidazolepalmitate.

After allowing the strings to remain in the calcium chloride solutionfor 5 minutes, each string was removed, rinsed in 0.1 percent calciumchloride solution, and placed in 0.1 percent (w/v) CHES solution,followed by soaking in a solution of 0.35 percent (w/v) poly(lysins) and10 to 15 percent (w/v) glycerine for 3 minutes. CHES solution is 2₁N-cyclohexylamine ethane sulfonic acid, manufactured by Sigma ChemicalCompany. Then, the calcium alginate strings were soaked again in the 0.1percent calcium chloride solution, followed by the CHES solution. Then,the string was immersed in 0.15 percent (w/v) sodium alginate solutionfor a further 3 minutes. Following this, the strings were removed anddried in air before packaging.

When portions of the above strings are implanted into periodontalpockets in the gum surrounding a portion of teeth which have beenafflicted with pyorrhoea, the hydrated strings or fibers release freemetronidazole on a continuous basis for at least a period of days, butin which the release of free metronidazole is more rapid when infectionis present, and of a reduced rate when the infectious symptoms recede,for the long term treatment of gum disease.

EXAMPLE 2

Sodium alginate (0. 5 percent w/w) was dissolved in double distilledwater by stirring at room temperature. Using a motor driven syringecontaining 10 ml. of an aqueous dispersion of 210 micrograms per ml. ofmetronidazole palmitate is extruded through a 16 gauge needle into anexcess (100 ml.) of 0.1 percent w/v calcium chloride solution. The cordwhich forms from the alginate material by this process is allowed toequilibrate for 5 minutes before removing carefully and immersing in 100ml. of 0.1 percent CHES solution for an additional five minutes.

The resulting cord was then washed by immersion an excess of 0.1 percentcalcium chloride solution for 30 minutes before transferring it to about50 ml. of 0.035 percent w/v poly(lysine) solution for three minutes withcareful stirring. The cord was then washed with 0.1 percent calciumchloride solution again, followed by a second immersion in a fresh 0.1percent portion of CHES solution for five minutes.

Then, the thread was transferred to a 0.1 percent sodium alginatesolution for three minutes before air drying at room temperature for 24hours. The thread was finally dried by desiccation over an anhydrouscalcium chloride for 48 hours at room temperature.

Equivalent results are obtained to the results of Example 1 when thecord or string is placed into a periodontal pocket in the gum of apatient next to teeth which have been infected with pyorrhoea.

It is possible to prepare the above cords of alginate having lengths upto about 70 cm. by this method, with the cords containing on the orderof 0.43-0.44milligrams of metronidazole palmitate per cm. of length.

EXAMPLE 3

Calcium alginate thread was made in accordance with the method ofExample 2, up through the step prior to immersion in 100 ml. of 0.1percent CHES solution for the first time. Then, the resulting cord wastransferred to a 1 percent solution of Chitosan (Protan Protosan MV) indouble distilled water and allowed to stand for 15 minutes. The cord waswithdrawn and air dried for 24 hours before drying over anhydrouscalcium chloride for 48 hours.

The resulting cord exhibited the characteristic described in thisapplication of providing a controlled release of metronidazolepalmitate, which can be converted in the presence of lipase enzyme intometronidazole.

That which is claimed is:
 1. A controlled release unit which comprises abiocompatible polymeric carrier material having carried therein acontrolled release agent, said controlled release agent comprising ametronidazole ester, said biocompatible polymeric carrier materialcomprising a hydrogel which defines ionic polymer units of one charge,said polymeric carrier material being coated with an outer coating whichcomprises a hydrogel which defines ionic polymer units of the oppositecharge to that of the hydrogel of the polymeric carrier, said outercoating acting as a controlled release barrier to limit generation ofmaterial for controlled release, and wherein said metronidazole ester isin an initial concentration sufficient to allow the controlled releaseof a bacterial growth inhibitory concentration of free metronidazole. 2.The controlled release unit of claim 1 in which said polymeric carriercomprises calcium alginate and said outer coating comprises a materialselected from the group consisting of pectin, chitosan, and chitin.
 3. Acontrolled release unit which comprises a biocompatible, polymericcarrier material having carried therein a controlled release agent, saidcontrolled release agent comprising a metronidazole ester present in aninitial concentration sufficient to allow the continuous controlledrelease of a bacterial growth inhibitory concentration of metronidazole,said carrier material being coated with an outer coating which comprisesa mixture of 70 to 95 parts by weight of poly(lysine) and 5 to 30 partsby weight, when applied, of a polyol plasticizer for said poly(lysine),said outer coating acting as a controlled release barrier to limitrelease of material.
 4. The controlled release unit of claim 3 in whichsaid polyol plasticizer is selected from the group consisting ofglycerin, sorbitol, and polyethyleneglycol.
 5. The controlled releaseunit of claim 3 in which said polymeric carrier is calcium or magnesiumalginate.
 6. The controlled release unit of claim 3 in which said outercoating carries an outermost hydrophilic alginate layer.
 7. Thecontrolled release unit according to claim 1 wherein said controlledrelease agent is a metronidazole ester which defines at least one estergroup of 10 to 18 carbon atoms per molecule, said metronidazole esterbeign present in said polymeric carrier material in an initialconcentration sufficient to allow the controlled release of at least abacterial growth inhibitory concentration of free antibiotic as ahydrolysis product from said metronidazole ester in response tobacterial lipase.
 8. The controlled release unit according to claim 7wherein said metromidazole ester is metronidazole palmitate.
 9. Thecontrolled release unit according to claim 7 wherein said growthinhibitory concentration of free antibiotic is at least three microgramsper ml. metronidazole.
 10. The controlled release unit according toclaim 3 wherein the controlled release agent is a metronidazole esterwhich defines at least one ester group of 10 to 18 carbon atoms permolecule, said metronidazole ester being present in said polymericcarrier material in an initial concentration sufficient to allow thecontinuous, controlled release of at least a bacterial growth inhibitoryconcentration of free antibiotic as hydrolysis product from saidmetronidazole ester in response to the presence of bacterial lipase. 11.The controlled release unit according to claim 10 wherein saidmetronidazole ester is metronidazole palmitate.
 12. The controlledrelease unit according to claim 10 wherein said growth inhibitoryconcentration of free antibiotic is at least 3 micrograms per ml.metronidazole.